B-RAF is a kinase that is part of the RAF-MEK-ERK MAPK pathway key to cell proliferation and survival. B-RAF mutations have been discovered in more than 7% of human cancers, including melanoma (43%) (see H. Davies, et al., Nature, 417 (2002), 949-54; D. R. English, et al., Cancer Epidemiol Biomarkers Prev, 17 (2008), 1774-80; G. V. Long, et al., Lancet Oncol., 13 (2012), 1087-95), thyroid (27%) (see Y. Cohen, J Natl Cancer Inst, 95 (2003), 625-7; E. T. Kimura, et al., Cancer Res, 63 (2003), 1454-7), colorectal (14%) (see H. Davies, et al., Nature, 417 (2002), 949-54; D. R. English, et al., Cancer Epidemiol Biomarkers Prev, 17 (2008), 1774-80; S. Ogino, et al., Gut, 58 (2009), 90-6; C. P. Vaughn, Genes Chromosomes Cancer, 50 (2011), 307-12), ovarian (15%) (see H. Davies, et al., Nature, 417 (2002), 949-54; S. E. Russell, J Pathol, 203 (2004), 617-9), and lung (2%) (see M. S. Brose, et al., Cancer Res, 62(2002), 6997-7000) cancers. More than 90% of the B-RAF mutations found in melanoma are a substitution of glutamic acid for valine at the 600th amino acid of the B-RAF protein chain (V600E), resulting in constitutive activation.
Clinical experience with B-RAF inhibitors such as vemurafenib and dabrafenib in melanoma patients has proven efficacious, which has validated the concept of targeting tumors dependent on B-RAF and MAPK signaling. Selective inhibition in melanoma patients harboring the B-RAF V600E mutation in their tumors yielded impressive objective response rates and prolongation of progression-free survival. However, the first generation of B-RAF inhibitors, including vemurafenib and dabrafenib, have a number of limitations, for example, 1) development of keratoacanthomas or cutaneous squamous cell carcinoma due to paradoxical increase of MAPK signaling through induction of B-RAF/C-RAF heterodimer in the context of mutated or activated RAS; and 2) limited clinical activity outside of melanoma with B-RAF V600E mutations (e.g., colorectal). Therefore, a second-generation inhibitor that can improve in these areas is highly desirable.
5-(((1R,1aS,6bR)-1-(6-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (free base, Compound 1) has been disclosed as a second generation B-RAF inhibitor, which has demonstrated potent inhibitory activity against RAF family of serine/threonine kinases. See WO 2013/097224 A1.

Compound 1 is a molecularly targeted therapeutic agent for the treatment of cancers with aberrations in the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway, including B-RAF mutations and K-RAS/N-RAS mutations, as either monotherapy or in combination with other cancer therapies. However, the relatively poor oral absorption of the free base of Compound 1 makes it unsuitable for drug product development.
It has been also found that the free base of Compound 1 was obtained originally as an amorphous solid based on the XRPD results of FIG. 1, and that the free base of Compound 1 is substantially insoluble in water with <LOQ at 0.001 mg/mL, and is slightly hygroscopic with 2.2% water gain at from 0 to 80% RH.
In addition, the synthesis of Compound 1 was inefficient. Various factors, for example, the requirement of chiral HPLC column for preparing optically pure isomer and the tendency of the free base of Compound 1 in amorphous form hindering the expulsion of impurities from the process, make large scale preparation and purification of Compound 1 a challenge.
Practically, it is difficult to predict with confidence which salts of a particular compound will be stable and suitable for pharmaceutical processing. It is even more difficult to predict whether or not a particular compound will form various crystalline solid-state forms, and to predict the physical properties of these crystalline solid-state forms.
Therefore, there is a great need for some forms of Compound 1 which have much better bioavailability and have chemical and physical stability during formulation and storage of this medication as well as a process suitable for large-scale preparation of Compound 1 with good quality and reproducibility is in great needs.